Format

Send to

Choose Destination
Cancer Chemother Pharmacol. 2015 Oct;76(4):813-9. doi: 10.1007/s00280-015-2856-y. Epub 2015 Sep 2.

Preclinical assessment of the interactions between the antiretroviral drugs, ritonavir and efavirenz, and the tyrosine kinase inhibitor erlotinib.

Author information

1
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
2
INOVA Comprehensive Cancer and Research Institute, Virginia Commonwealth University, INOVA Campus, Falls Church, VA, USA.
3
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
4
Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
5
Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
6
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans Street, Bunting-Blaustein Cancer Research Bldg. Room 1M52, Baltimore, MD, 21231-1000, USA.
7
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans Street, Bunting-Blaustein Cancer Research Bldg. Room 1M52, Baltimore, MD, 21231-1000, USA. mrudek2@jhmi.edu.

Abstract

PURPOSE:

Prevalence of non-AIDS-defining cancers (NADCs) has increased in the era of potent antiretroviral treatments. Incidence rates of NADCs now exceed AIDS-defining cancers in HIV-positive patients. Treatment of NADCs may be complicated by interactions between antiretrovirals and chemotherapy mostly via inhibition or induction of CYP3A4. Erlotinib is used to treat non-small cell lung and pancreatic cancer and is primarily metabolized by CYP3A4 into multiple products including the active metabolite (OSI-420). Preclinical in vivo assessment was performed to gain a better understanding of CYP3A4-mediated interactions between antiretrovirals and erlotinib.

METHODS:

Erlotinib (50 mg/kg p.o.) was administered to male FVB mice in the presence and absence of dexamethasone (10 mg/kg p.o. QDx4), efavirenz (25 mg/kg p.o. QDx4), ketoconazole (50 mg/kg p.o.), or ritonavir (12.5 mg/kg p.o.). Blood samples were collected to characterize exposure (AUC).

RESULTS:

Administration of erlotinib with CYP3A4 inducers (dexamethasone) and inhibitors (ketoconazole and ritonavir) resulted in significant alterations in erlotinib exposure. Ketoconazole and ritonavir resulted in a 1.7- and 3.0-fold increase in erlotinib AUC, respectively, while dexamethasone results in a 0.6-fold decrease in erlotinib AUC. The CYP3A4 inducer efavirenz did not have a significant effect on erlotinib exposure.

CONCLUSION:

CYP3A4 inducers and inhibitors altered the exposure of erlotinib. Until a definitive clinical trial is performed, erlotinib should be used with caution in patients on a ritonavir-containing antiretroviral regimen, while standard doses may be appropriate for patients on an efavirenz-containing antiretroviral regimen.

KEYWORDS:

AIDS; Drug interaction; Efavirenz; Erlotinib; Ritonavir

PMID:
26330331
PMCID:
PMC4577782
DOI:
10.1007/s00280-015-2856-y
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Grant support

Publication type

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Springer Icon for PubMed Central
Loading ...
Support Center